美国FDA指南-中文版

《美国FDA认证与申办指南》 权威资讯系列 《合成原料药DMF起草大纲》 使用说明: 1、本大纲是为了帮助我公司客户把握DMF的整体内容而准备 的,由于DMF内容繁多,从整体上了解内容框架和组成部分,对于理解FDA对DMF的要求和意图非常有必要; 2、根据FDA的要求,凡是本大纲提到的内容,原料药制造商均 应该提供。因此,客户务必依照规定提供尽可能详细的内容。3、本大纲的内容和相关要求能够确保客户目前的运作达到FDA 的cGMP标准,因此,准备DMF的过程,也使客户按照FDA的要求进行整改和提高的过程,这些都为FDA未来的现场检查打下良好基础; 4、凡是本大纲中提到的非技术性具体内容要求,请参照本公司专有的与此大纲配套的相关DFM指导性文件,包括《FDA药物主文件指南》、《关于在药品递交中递交的有关原料药生产的支持文件的指南》、《药物申办中质量管理方面通用技术文件格式与内容要求》; 5、凡是本大纲中提到的技术性具体内容要求,如杂质、稳定性、验证等具体技术要求,请参照本公司专有的FDA相关技术标准文件,包括《原料药认证指南》、《制剂认证指南》、《化学药物稳定性指南》、《化学药物杂质指南》、《化学药物化验与合格参数指南》、《化学药物验证指南》等; 《合成原料药DMF起草大纲》 一、公司和生产场地的基本描述 1、第一类的DMF文件建议由位于美国之外的人提供,以帮助FDA对他们的生产设施进行现场检查。DMF文件应描述生产场地、设备能力、生产流程图等。A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout. 2、第一类的DMF文件对美国国内设施通常不需要,除非该设施没有登记并定期接受检查。A Type I DMF is normally not needed to describe domestic facilities, except in special cases, such as when a person is not registered and not routinely inspected. 3、场地的描述应包括面积、实际地址以及表明该场地与最近的城市的距离的地图。提供该场地的鸟瞰图和平面图。The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful. 4、主要生产和加工区域的平面图对于理解整个生产布局会有帮助。应当描述主要设备的生产能力、用途和位置。通常不用描述设备的制造商和型号,除非特别新或独特的设备。A diagram of major production and processing areas is helpful for understanding the operational layout. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique. 5、公司主要的组成部门结构图,包括总公司和生产场地的关键生产、质量控制、质量保证岗位,A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful. 二、原料药的物理和化学特征 1、特性Properties 相关法规要求对原料药的物理和化学特征做出详细描述。该要求可以通过提供下述信息来满足:名称(通用名、化学名、编码等)、化学摘要服务(CAS)编码、性状描述(如:外观、颜色、物理状态)、分子式和分子重量、结构式(包括离子状态)、立体化学(找出手性中心、顺式反式异性等)、对映结构体比率(如:外消旋物、规定的异构体、对映异构物和固态形式的混合物)、溶解度概况(水溶性的或非水溶性的)、分配系数、溶液pH值、解离常数、熔点或沸点、折射率、比重。对于蛋白质原料药,参见:“CRC生物化学和分子生物学手册”“酶学方法”和有关描述蛋白质特性的专论。The regulations require a full description of the physical and chemical characteristics of the drug substance. This requirement may be satisfied by the submission of information such as the following: name (generic name, chemical name, code number); Chemical Abstracts Service (CAS) number if available; description (e.g., appearance, color, physical state); molecular formula and molecular weight; structural formula (including ionic state if applicable); stereochemistry (identifying chiral centers, cis-trans isomerism, etc.); enantiomer or solid-state form ratios (e.g., for racemates, and for defined admixtures of isomers or enantiomers or solid-state forms); solubility profile (aqueous and nonaqueous as applicable); partition coefficients; solution pH; dissociation constant(s); melting or boiling point; refractive index; specific gravity. For drug substances that are proteins, see the "CRC Handbook of Biochemistry and Molecular Biology," "Methods in Enzymology," and related monographs for how protein properties may be described. 并非所有的递交都要求上述信息,额外的信息也可能需要,特别是随着生产工艺的复杂性的增加。The items above are not necessary or appropriate for all submissions. Additional information may be required, particularly as the state of the art progresses. 2、结构Structure 对于结构的说明(如:相关数据和其解释)应当基于一个合适的物理和化学检测结果。这包括以下内容:元素分析;质谱分析(MS);核磁共振(NMR);紫外(UV)和红外(IR)光谱学;分子量测定;立体化学和构象分析(如:光学和几何学异构体);X光分析;降解分析(如:氨基酸排序和分析);色析图谱;其它检验(如:功能团分析,衍生作用,络合形式等) The elucidation of structure (e.g., the data and its interpretation) should be based on appropriate physical and chemical test results. These may include the following: elemental analysis; mass spectrometry (MS); nuclear magnetic resonance (NMR), ultraviolet (UV), and infrared (IR) spectroscopy; molecular weight determination; stereochemistry and configurational or conformational analysis (e.g., optical and geometric isomers); X-ray analysis; degradative analysis (e.g., amino acid sequencing and/or analysis); chromatographic profile; other tests (e.g., functional group analysis, derivatization, complex formation). 同样,并非所有以上条目都是必须的或适用于所有情况,所列条目也不是完全的(工艺过程更加复杂和新原料药需要时,也许需要做出更多的分析)。实际数据及其解释的细节应当放在“参考标准”章节(参见II.F.2, 和 3)。Again, not all items are necessary or appropriate in all cases, and the listing should not be considered limiting (i.e., more analysis may be required as the state of the art progresses and the nature of the new drug substance demands). The actual data and the details of its interpretation should be placed in the section for Reference Standard (see II.F.2, and 3.). 三、原料药的稳定性 相关法规要求对原料药的稳定性做全面的描述。具体要求,参见“关于提交人类用药品和生物制品稳定性文件的指南”。The regulations require a full description of the stability of the drug substance. See the "Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics" for assistance in fulfilling this requirement. 四、原料药的生产 1、起始 材料 关于××同志的政审材料调查表环保先进个人材料国家普通话测试材料农民专业合作社注销四查四问剖析材料 的控制程序control procedures for starting materials 应当列出起始原料。应该提供其承诺的标准和用来判定其特性、质量和纯度的检验方法。分析检验方法应当简要描述。起始原料的来源通常无需说明,但有时会要。Starting materials should be listed. Acceptance specifications and tests defining identity, quality, and purity should be provided. The analytical test methods should be briefly described. The source of the starting material need not be identified, but may be requested. 对起始材料应该进行鉴别和含量测定分析。在某些情况下,当杂质(如芳香化合物的异构体)被混入原料药时,应提供纯度档案(如包括杂质的定量与定性色谱图)。通过定期与不定期的核查与验证来评估原料供应商提供的产品质量是稳定的,供应商提供的质量保障声明应该包括相关的规格和结果,并应该注明用于检测的分析方法。A specific identity test should be performed, as well as an assay, with limits for impurities. In those cases where impurities (e.g., positional isomers of aromatic compounds) could be carried through to the drug substance, a purity profile should be provided (e.g., chromatography with quantitation/identification of impurities). Assurances or statements of quality from the supplier are acceptable for the profile, provided that the manufacturer establishes the reliability of the supplier's analyses through validation, initially and at appropriate intervals. These statements from suppliers should include specifications and results and should indicate the type of method 2、试剂、溶媒和辅料控制Reagents, solvents, and auxiliary materials controls 应列出合成原料、溶媒的内容。标明以上原料、溶媒的规格和检验方法,并应该提供相关的质量声明。递交者应当注明具体的检验方法(除非忽略这种检验可被认为是正当的)。无论是原料供应商还是递交者,进行额外检验时,应该依据该化学成分在合成中的作用进行。例如,对于用来中和合成反应混合物中多余的酸用得碱时(如氢氧化钠),通常不需要进行的纯度检测。相反,用于关键环节的光学活性的有机酸(如:某种酸的对映体),则需要这样的额外检测。These chemicals should also be listed. The specifications and test methods for each such material should be stated, and/or a statement of quality provided. The applicant should describe the specific identity test performed (unless omitting such a test has been otherwise justified, e.g., because of hazard). The extent of additional testing performed – whether by the supplier or by the applicant -- should be based on the role of the chemical in the synthesis. For example: a base (e.g., sodium hydroxide) used to neutralize excess acid in a synthetic reaction mixture would not normally require extensive purity testing; in contrast, an optically active organic acid used in a resolution step (e.g., one enantiomer of dibenzoyltartaric acid) would require such additional testing. 3、详细的合成信息 递交者应当提供完整的合成信息,从起始原料到最终成品原料药。有关描述应当包括整个合成过程的流程图以及每一合成步骤的说明)。An applicant should provide complete information on the synthesis, from starting material(s) to the bulk new drug substance. The description should contain a diagrammatic flow chart of the whole synthesis and a written statement for each step of the synthesis. (1)合成流程图Flow chart of the synthesis. 合成的流程图应该包括以下内容The flow chart typically should contain the following: (1) 反应物和产品的化学结构(如:起始原料、中间体,以及引入到结构中的分子)Chemical structures of reactants (i.e., starting materials and intermediates, and also molecules incorporated into the structure) and products; (2) ) 立体化学结构,如果有立体化学构形 Stereochemical configurations, where applicable; (3) 中间体(未分离的或已分离的)Intermediates (either in situ or isolated); (4) 溶媒、催化剂和试剂Solvents, catalysts, and reagents; 反应所产生的产品与副产品混合比率(如:两个或更多异构体)应该显示在流程图上。重要的副产品和杂质,尤其是那些干扰分析过程或有毒性的,应当被分别表示出来(参见:第II.D.2.c. 和 II.F.3.)A ratio or mixture of products (e.g., two or more isomers) produced by a reaction should be shown in the flow chart. Significant side products and impurities, particularly those that interfere with the analytical procedures or are toxic, should be illustrated separately (see sections II.D.2.c. and II.F.3.). (2)合成描述Description of the synthesis 每一个合成步骤的书面描述以及更详细的最后加工步骤的描述应该包括以下内 容The written statement for each step of the synthesis, with greater detail included toward the final steps of the process, should include the following: (1) 用于反应的典型设备Typical equipment used for the reaction; (2) 反应物(本步骤所使用的起始原料或中间体,包括化学名称和数量) Reactants (starting material or intermediate used in the step, with chemical names and amounts); (3) 溶媒、催化剂和试剂(注明化学名称和数量)Solvents, catalysts, and reagents (chemical names and amounts); (4) 反应条件(温度,pH值,时间,压力等)Conditions (temperature, pH, time, pressure, etc.); (5) 反应完成的检测,如果有的话。Tests for completion of reaction, if employed; (6) 分离的程序Workup and isolation procedures; (7) 原料药和中间体的纯化过程,如果有。Purification procedures for drug substance and for intermediates, if employed; (8) 收率范围(初品和/或精品的重量和百分比)Yield ranges (crude and/or purified; weight and percent). 应该提供原料药最后合成、分离和提纯的详细信息。(参见第II.D.2.c部分关于原料药提纯的内容)。The final step of the synthesis and the isolation of the crude new drug substance, as well as its purification, should be provided in full detail. (See section II.D.2.c below regarding purification of the drug substance.) 除了提供合成的书面描述,还包括经过确认的操作参数范围(参见第II节-E工艺控制)和第 IV节[CGMP])以及预期收率,递交者同时要提供实际操作的书面实例(BPR),明确指出它是供审阅官参考。这个例证不应该仅仅是批生产纪录的拷贝,它应该包括更详细的内容。Besides providing a written description of the synthesis which includes verified ranges for the operating parameters (refer to section II-E [Process controls] and section IV [CGMP]) and for the expected yield, the applicant should provide a written example of actual practice, clearly identified as an example for the reviewer's information. This example should not be merely a copy of batch records but should contain more detail. 应该描述所采取的替代措施(如:替代起始原料、反应物、溶媒、条件、催化剂、分析和提纯过程)。应该提供每一不同合成方法所生产的原料的比较性分析数据Any alternate method or permissible variation that may be employed (e.g., alternate starting materials, reactants, solvents, conditions, catalysts, isolation, and/or purification procedures) should be reported. Comparative analytical data for the material produced by each variant synthetic method should be provided. (3)原料药的纯化Purification of the drug substance 应该详细描述原料的提纯情况和其从最终反应混合物中分离的情况。其中应该包括以下内容:The description of the purification of the crude new drug substance and its isolation from the final reaction step mixture should be given in detail, and should include: (1) 原料药的收率范围The yield ranges of the crude product; (2) 任何用于判断原料产品纯度的检验。(参见下面第6条)Any tests performed on the crude product to determine its purity (see item 6, below); (3) 详细的分离和纯化过程的 记录 混凝土 养护记录下载土方回填监理旁站记录免费下载集备记录下载集备记录下载集备记录下载 (如:对于重结晶过程:所使用的溶媒,与原 料产品相关的溶媒的数量,溶媒在热时候是否被过滤,是否使用了脱色剂,冷却温度与和最终温度,母液的使用和再使用,溶媒是否进行了二次回收。 A detailed description of the isolation and purification procedures (e.g., for recrystallization: the solvent used, the quantity of solvent in relation to the amount of crude product, whether it is filtered while hot, whether a decolorizing agent is used, the rate of cooling and the final temperature, the use or re-use of any mother liquors, and if second crops are obtained); (4) 替代的提纯步骤(参见II.D.2.b.中的最后一段;参见II.G)Alternative purification procedures (see the last paragraph of section II.D.2.b.; see also section II.G.); (5) 提纯产品的收率范围(重量和百分比)The yield range (weight and percent) of the purified product; (6) 证明提纯过程增加纯度的有关证据,例如色析法的前后对比Evidence demonstrating that the purification procedure improves the purity, such as before-and-after chromatographic illustrations. 当提纯工艺被验证后,只需提供最初产品批次的检验相关信息。This testing and information may be necessary only on initial production batches, once the purification process has been verified or validated. (4)合成的变化Changes in the synthesis 相关合成的变化应该作为DMF的补充来提交。为改变新药物递交(NDA)中已经批准的有关原料药的合成方法,制剂递交者也需要提交一个批准的补充文件,这包括有关溶媒的改变。Proposed changes in the synthesis should be submitted to the application as a supplement for an approved NDA or as an amendment to an IND, a DMF, or a pending NDA. An approved supplement is required [21 CFR 314.70(b) (1) (iv)] to change the method of synthesis approved in the NDA for the drug substance, including a change in solvents. 当合成的路线发生改变时(如:反应和中间体与新药递交(NDA)所批准的相关内容不同时),应该提供每一合成路线的比较分析数据(如:完整的纯度档案数据)。下面我们将讨论有关变化旨在重新定义起始原料的情况。When the route of synthesis is changed (i.e., reactions and/or intermediates are different from those approved in the NDA), comparative analytical data (i.e., a complete purity profile) for the drug substance made by each route should be provided. A special case, where the proposed change is to redefine the starting material, is discussed below. 当用于原料药最终结晶的溶媒发生变化时,应该检查原料药有关晶形和溶剂化物的变化;参见II.G。原料药必须符合有关晶形和溶剂化物的原定规格。When there is a change in the solvent used for the final crystallization of the new drug substance, the new drug substance should be examined for changes in crystalline form and/or solvation; refer to section II.G. The new drug substance must meet its original specifications for crystalline form and/or solvation. 有关其它的反应和提纯的溶媒改变也需要一份补充递交,补充递交中应该提供该改变可以产生同等质量和纯度的产品(化合物或中间体)的证据,但无需考虑形态学问题。Solvent changes for other reaction steps or purifications also require a supplemental application. The application should contain evidence that the change affords material (compound or intermediate) of equivalent quality and purity, but morphology need not be considered. 如果递交者想缩短新药递交(NDA)中批准的合成方法或者通过重新定义起始原料时,则需要提交一个补充文件(21 CFR 314.70(b) (1))。该起始原料是一种可从商业渠道获得的用于合成的化合物,该化合物必须是新药递交中(NDA)批准的中间体,而且,必须满足起始材料"b" 和"c"标准要求。An approved supplement is required (21 CFR 314.70(b) (1)) if an applicant wants to shorten the synthesis approved in the NDA or develop a new synthetic method by redefining the starting material, in order to employ a compound later in the synthesis that has become commercially available. This compound must have been an intermediate in the approved NDA synthesis, and must meet both the "b" and "c" criteria for starting material. 在完成原料药的合成之前,该化合物至少在两个完整的合成阶段前使用。依据所引用的参考文献(应该提供相关拷贝)的充分性,需要提供起始原料的纯度和特性等额外信息,这包括足够的文献资料(如提供的复印件)。The compound should be used at least two full steps before the new drug substance if possible (i.e., it should be prior to the final intermediate). Additional information on the characterization and purity profile of the starting material may be needed, depending on the adequacy of the literature references cited (copies should be provided). 对于学术期刊所引用的化合物,详尽的出版材料就够了(如:有关杂质检验的额外信息)。在有关专利中所规定的化合物,需要提供其完整的特性和纯度档案。应该描述用于检验每一批新起始原料的分析检测程序。建立一个通用的检验 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 通常就可以了。For compounds cited in journal articles, an elaboration of the published material (i.e., additional information about testing for impurities) may suffice. For compounds described in patents, both complete characterization and a full purity profile will usually be needed. Analytical test procedures used to qualify each new source/supplier of the new starting material should be described. A general testing protocol may be suitable. 递交者应该通过直接的比较(如:通过分析和使用)证明该化合物与用于临床试验用的新原料药等效,同时应该证明该化合物的符合承诺的标准。使用至少是试验性规模(如:要大于实验室规模)。The applicant should demonstrate by direct comparison (i.e., both by analyses and by a use test) that the compound is equivalent to the material used to make the new drug substance employed in the clinical trials, and that the acceptance tests and specifications for the compound are adequate. The use test should be at least on a pilot scale (i.e., larger than bench scale). 应该提供用该材料所生产的前三批产品的完整检验结果。该检验的广度和深度要和用于检测一个新的参考标准品的相同。A commitment to submit results from thorough examination of the first three full-scale batches made with the material should be provided. The examination should be similar in scope and extent to the testing involved in qualifying a new reference standard. 对于依据联邦法典21 CFR 314.70(c) (3)所做的改变类型,只要有对合成过程的充分描述文件,就可以。这样的改变,无需FDA的事先批准就可以执行。For changes of the type permitted by 21 CFR 314.70(c) (3), an adequate synthesis description on file would facilitate a conclusion that changes in site of manufacture of the new drug substance do not require prior FDA approval for implementation. 4、参照标准品Reference Standard 原始递交的申报文件应该包括任何所使用的参照标准品的制备过程的描述,包括对提纯步骤的描述,参见II.F.3.The original application should include a full description of the preparation of any reference standard substance used, including the description of the purification steps. See also section II.F.3. II.D.4. 五、生产过程的控制 1、中间体和生产过程的控制Intermediates and In-process controls 相关法规要求在合成过程中选择一些中间环节实施控制(检测项目与参数要求),以保证合成和提纯工序顺利进行,并保证检测后的中间体适合于以后的加工。申请者可以根据对整个合成工艺的开发和确认的经验,自行确定对那些中间体或加工环节进行检测及进行那些检测项目。在早期的开发阶段,每一个步骤通常都进行了检验(至少是对反应的内容),每一个中间体至少都进行与纯度有关参数的测定,包括纯度的估计。随着合成经验的积累,应选择关键的反应步骤和中间体进行监控。在递交新药申请(NDA)时,生产过程的控制点应该已经选定,相关控制参数和检验方法也已确立,以满足法律的要求。The regulations require that controls (specifications and tests) be employed at selected intermediate stages of the synthetic process to assure that the synthetic and purification procedures are operating properly and that the intermediate tested is suitable for subsequent processing. The choice of which intermediate(s) or steps in the process to test, and the kind of testing required, are the responsibility of the applicant based on his experience during the development and verification of the total synthetic process. In early development work, every step would usually have been examined (at least for extent of reaction) and every intermediate at least partially characterized with some estimate of purity. As experience is gained with the synthesis, the critical reaction steps and intermediates to be monitored are selected. At the time of NDA submission, in-process control points should have been selected and appropriate specifications and tests established to meet the requirements of the regulations. 这里描述的整个操作都是合成工艺验证的一个部分。应当解释选择相关控制点和中间体的根据。应当证明控制参数和检测方法对合成过程的控制是充分的。应当依据相关控制点(控制参数和检测方法)来提供控制参数范围的书面描述。通常,较宽的参数范围需要更严格的控制(参见:II.E.b.(回收和再加工))。在新 药申请(NDA)被批准后,随着经验的积累,可能需要修改生产过程的控制程序。该控制程序的改变需要额外的验证(参见:IV)。This whole operation is part of the process validation of the synthesis. The basis for selecting control points and intermediates should be explained, and the adequacy of the specifications and tests to control the synthetic process demonstrated. The ranges for the operating parameters in the written description of the synthesis should be chosen in light of the controls (specifications and tests). Generally, broad operating ranges will require stricter controls. (See also section II.E.b. (recovery and rework) below.) With additional experience subsequent to NDA approval, the choice and nature of in-process control procedures may require modification. Changes in in-process control procedures will require additional validation (see section IV). 设计控制为得是:Controls may be designed to (a) 证明已获得了想要生产的产品demonstrate that the desired product has been obtained; (b) 确定关键的物理特征(如:熔点、旋光度等)determine a key physical property (e.g., melting point, optical rotation, etc.); (c) 确定中间体的纯度和杂质determine purity/impurity of the intermediate; (d) 确定收率是限定在通常的操作范围之内determine that the yield is within the normal operating range. 在某些情况下,对中间体的控制是不可行的(如:它们处于溶液状态或直接加工成下一个化合物)。如有可能,检测也可仅限于对合成过程的监控(如:反应是否完成)。In some cases no controls for the intermediate may be feasible (e.g., where they are held in solution, or are directly processed to the next compound). When appropriate, testing may consist only of a test designed to monitor the progress of the synthesis (i.e., reaction completion). 上面所列的部分或全部生产过程中的控制在每一个控制点都应该符合控制检测的要求。关键、核心和最后的中间体(参见:术语表)通常至少应当符合以上所列过程控制的要求。为减少最终的大规模清除,从第一个中间体到原料药本身,中间体的纯度应该逐渐提高。Some or all of the above kinds of process controls should be met at each point selected for in-process control testing. Pivotal, key, and final intermediates (see Glossary, and below) would ordinarily require at least the in-process controls listed above. To eliminate the need for heroic final cleanups, it is expected that the degree of purity of intermediates will increase progressively, from the first intermediate on to the drug substance itself. 2、关键中间体(见术语表)Pivotal intermediate(s) (See Glossary.) 应该用足够的细节(如详细描述其特征)描述任何关键中间体,并作为控制参数与检验的一个部分,对其进行严格的检查,其中还包括通过层析法,以避免忽略 由替代合成方法产生的杂质。如此严格的检验无需经常进行,但是当供应商或合成发生改变时,要做以上检查。当关键中间体接近成为最终中间体时,对其进行的检测程度和纯度要求也应该增加Any pivotal intermediate should be described in adequate detail (i.e., be well characterized) and be subject to rigorous examination procedures as part of the specifications and tests, including thorough chromatographic examination so as to avoid overlooking impurities arising from alternative syntheses. Such rigorous examination need not be routine but may be needed in special circumstances such as when the supplier or synthesis is changed. The degree of testing and the level of purity required for a pivotal intermediate should increase as its position in the synthesis scheme approaches the final intermediate. 3、核心中间体(参见术语表)Key intermediate(s) (See Glossary.) 对核心中间体,应制定充足的规格,以保证能生产出所需的分子结构和纯度的最终产品。检测程序应该能够标明,所需要的转换(如:手性的引入或立体定向反应)已经按照预想的方式发生,并在预期的收率范围内,同时通过定量分析表明,不需要的材料(如:异构体、副产品、起始原料)已经限制在既定限度之内。The specifications should be adequate to assure that the molecular architecture necessary for the final product, as well as the requisite degree of purity, have been attained. Test procedures should thus show that the desired transformation (such as introduction of chirality, or a stereospecific reaction) has occurred in the manner expected and within the normal yield range expected, and show by quantitative determination(s) that undesired materials (e.g., isomers, by-products, starting materials) are within established limits. 4、最终中间体(参见术语表)Final intermediate (see Glossary.) 关于最终中间体的规格和检验应该与原料药的规格和检验同样广泛和严格,因为这是最终反应前的最后监控纯度和杂质的机会。Specifications and tests for final intermediate should be nearly as extensive and stringent as those for the new drug substance itself, because this is the last opportunity to monitor purity and impurities before the final reaction. 5、返工Reprocessing 对不符合加工规格要求的中间体,可以按照新药申请(NDA)中所描述的提纯方法进行进一步提纯。当采用替代的提纯方法时,获得的产品应象第一次一样,接受最后加工操作与检验。Intermediates which do not meet in-process specifications may be further purified using the same purification procedure described in the NDA. When an alternate purification procedure is used, the recovered material should be subjected to the same final processing operation and the same testing as for the first time. FDA认识到,有时操作条件(如时间和温度)会偏离新药申请(NDA)中的描述。应当制定一个方案,规定当反应条件或操作控制参数超出通常的范围时(如:偏离或较小的背离),应当采用什么样的程序,来使该批中间体或原料药合格。该方案应该为确保该批产品合格所使用的额外分析检验。这样的检验应该比日常要求的控制参数和检验范围更广。如需要,可以使用非常规分析方法。例如,对超出正常条件的新原料药批产品(如:反应条件超出一般范围),应该按使用分析标准参照品是否合格的程序来进行检验。FDA recognizes that operating conditions (such as time and temperature) occasionally deviate from the NDA description. A protocol should be provided for the procedure which will be used to qualify the batch of intermediate or drug substance as meeting specifications when reaction conditions or operating parameters fall outside the typical/normal range (i.e., "excursions," or minor deviations). The protocol should describe the additional analytical testing which will be used in qualification of the batch. The testing should be more extensive than required by routine specifications and tests and may include, as appropriate, the use of nonregulatory analytical methods. For example, batches of new drug substance in this category (i.e, when reaction conditions are outside the norm) should be examined by discerning analytical procedures such as those used for Reference Standard qualification. 对于母液的处理和二次回收应当制定控制程序并进行描述。参见II.D.3.d.。虽然重复使用母液和二次回收是常见的并被CGMP接受,当杂质含量积累时,它并不完全被接受的。同时,广泛的回收母液或反复回收是不鼓励的(参见:CGMP 第IV节和“关于大宗药用化学物制造的现场检查指南”)。In-process control procedures should be established and described for the handling of mother liquors and recovery of second crops when this is done; see section II.D.3.d. While the re-use of mother liquors and recovery of second crops may be common/normal practice and is acceptable from a CGMP viewpoint, it is not necessarily acceptable (i.e., when impurity levels build up), and extensive recycling of mother liquors or repeated recoveries of additional crops is discouraged (refer to section IV (CGMP) and the "Guideline for Inspection of Bulk Pharmaceutical Chemical Manufacture" in this regard.) 母液的回收程序应该包括在批产品生产纪录中。新药申请(NDA)中应规定对不符合标准的原料药的再加 工程 路基工程安全技术交底工程项目施工成本控制工程量增项单年度零星工程技术标正投影法基本原理 序,这一过程通常是通过从最终溶媒中进行一次或多次再结晶来完成。不需要额外的分析检验。The recovery procedures should be included in batch production records. Provision should be made in the NDA for the typical and usual reprocess procedure for drug substance which fails to meet specifications, usually by one or more additional recrystallizations from the final solvent. Extraordinary analytical examination is not required in this case. 不符合既定标准的单一批产品可以通过适当的程序来纯化,然后按照新药申请(NDA)中所描述的最终提纯过程处理,前提是,用于最终纯化的材料纯度,与通 常加工情况下的材料纯度相同。A single batch of drug substance which fails to meet specifications may be purified by an appropriate procedure and then processed by the same final purification procedure described in the NDA, provided that the purity of the reprocessed material being so treated in the final purification step is as good as the normal drug substance at this stage of processing. 一些可再利用的散装原料药(如:累积的未使用的分析样品,未使用的批产品,由客户退回的产品)可以用同样的方法加工。Some types of bulk drug substance for salvage (e.g., accumulated unused analytical samples, unused portions of lots, bulk returned from customers) may be processed in this fashion. 这些再加工的原料药应该接受如上面所描述的(如:对稍微背离正常加工条件下所生产出的原料药)额外分析检验。再加工操作和其原因应该记录。依照目前法规,在没有额外提纯(经过新药申请(NDA)所描述的最终提纯步骤的处理)情况下,为使不合格的批可再利用而进行的混批是不能接受的。Such reworked drug substance batches should be subjected to additional analytical examination, as indicated above (i.e., for drug substance resulting from minor deviations of process conditions). The rework operation, and the reason for it, should be documented. The blending of batches or lots for the purpose of salvaging unsatisfactory batches, without subsequent additional purification by an appropriate procedure and processing by the final purification step described in the NDA, is not permitted under current guidelines. 如果在新药申请(NDA)中没有提到,要经常使用某一标准的(经过验证的)再加工程序,对不合格原料药进行处理,那么,应提供这方面的补充资料。参见“化学原料药生产现场检查指南”。If not part of the original NDA, a supplement should be submitted to the NDA when a standard (validated) reprocessing procedure for unsatisfactory bulk drug substance is to be routinely employed; refer to the "Guide to Inspection of Bulk Pharmaceutical Chemical Manufacturing." 当原料药要从制剂中回收时,应当参见“关于提交制剂产品生产和控制文件的指南”。这样的操作需要提供补充资料。When drug substance is to be recovered from dosage forms, reference should also be made to the "Guideline for Submitting Documentation for the Manufacture of and controls for Drug Products." This type of operation will require a supplement. 六、成品的控制 相关法律要求制定规格参数和分析方法(如:新原料药的放行控制),以帮助确保原料药的特性、浓度、质量和纯度达到要求并且每批均一致。应该提交以下信息,以定义这些控制参数和检验方法。The regulations require specifications and analytical methods (i.e., release controls for the new drug substance) to help assure that the proper identity, strength, quality, and purity of the drug substance have been attained and are consistent from batch to batch. The following information should be submitted to define these specifications and test methods: 1、抽样Sampling CGMP条例中有关于抽样的描述(参见:IV)。应该描述抽样 计划 项目进度计划表范例计划下载计划下载计划下载课程教学计划下载 ,制定该计划的依据;抽样应该满足相关统计学的考虑。Sampling requirements are covered by CGMP regulations (see section IV). The sampling plan should be described, giving the basis for the plan; it should satisfy appropriate statistical considerations. 2、放行控制Release controls 对放行中可能使用的规格和检验标准,举例如下:Examples of specifications and tests that may be applicable are as follows: (1) 外观/描述Appearance/description (2) 物理特性(如:熔化范围、旋光率、折射率、晶形、粒度) 对有手性中心或其它结构要求的原料药,相关的控制参数和检验应该能够保证,所生产出原料药具有治疗活动所需特征。参见第III部分。Physical properties (e.g., melting range, specific rotation, refractive index, crystalline form, particle size). For drug substances with chiral centers or other configurational requirements, the specifications and tests should assure that material (whether a single enantiomer or isomer, a racemate, or a known ratio of isomers) with the requisite properties for therapeutic activity has been produced. See section III in this regard. 同样,当药物的固态特性(参见II.G),如:多态现象或分子大小,会影响生理学或药理学活性(如:药物的生物效率),则相关控制参数和检验应该提供对这些特性的适当的限度(无论是单独形式或混合物形式)。Similarly, when the solid-state properties (see section II.G.) of the new drug substance, such as polymorphism or particle size, are known to affect physiological or pharmacological activity (i.e, bioavailability of the drug product), the specifications and tests should provide appropriate limits for these properties (whether as single forms or as admixtures). (3) 鉴别检查(如:红外线(IR)、核磁共振的(NMR)和质谱测定法(MS)) Specific identity test(s) (i.e., infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS)). 鉴别检查应该能够区别新原料药和相关化合物。如果只进行一个鉴别检验,应当首推红外线(IR)光谱(溴化钾颗粒)。其它的鉴别检验(如:紫外光谱,各种色析法的相对保留时间[R[f] 或T[R]值],将被认为是确认性的而不是专属性的。鼓励进行额外的(确认)检验,但多个确认性鉴别将能取代一个特定性鉴别。The specific identity test(s) should be capable of distinguishing the new drug substance from related compounds. If only one specific identity test is performed, an IR spectrum (KBr pellet) is preferred. Other identity tests (such as UV spectra, or relative mobility [R[f] or T[R] values] by various chromatographic methods) are considered confirmatory rather than specific. Doing additional (confirmatory) tests is encouraged; however, doing several confirmatory tests will not substitute for a specific identity test. (4) 杂质档案和限度(也就是说明在原料中存在的起始原料、中间体、副产品、降解品、溶媒和其它杂质的情况,以及其它关于这些杂质的限度)Impurity profile and limits (i.e., tests to detect, identify, and quantitate the presence of starting materials and intermediates, by-products, degradation products, solvents, and other impurities, as well as proposed/recommended limits for such impurities). 如果通过适当的努力可达到的话,对杂质不仅应当检测其含量,还应当确认其是什么化合物。Impurities should not only be detected and quantitated, but should also be identified and characterized when this is possible with reasonable effort. 在分析方法开发和验证中,应当解决下述问题 During the development and validation of the analytical methods the following concerns should be addressed: (1) 该方法能够检测杂质与溶解杂质(如:方法的灵敏性和专属性)Ability of the method to detect and resolve impurities (i.e., the sensitivity and specificity of the methods); (2) 定量和线性Quantitation, and linearity of response; (3) 杂质特性(如:起始原料、中间体、降解物)nature of the impurity (e.g., starting material, intermediate, degradation product); (4) 分类(如:主要的或次要的、毒性的或较小毒性的、已知或未知的[如:还未被从化学上确定的]) classification (e.g., major or minor, toxic, known or unknown [i.e., not yet chemically identified or characterized]); (5) 杂质的分离纯化与结构证明(如:鉴别和特征),需要时与权威样品进行比较isolation, purification, and proof of structure (i.e., identification and characterization), including the preparation of authentic specimens for comparison when needed. 在申请文件中杂质部分应该表明,上述各项都已考虑(如:新原料药中的杂质检验是充分的,并已做了合理的努力来鉴别和描述它们的特征)。The section on impurities in the application should demonstrate that all the above points have been considered (i.e., that the examination of the new drug substance for impurities has been adequate, and that reasonable efforts have been made to fully identify and/or characterize them). 应该提供:1、已知杂质的结构;2、杂质的分析方法验证;3、杂质的规格与检测方法,参照II.F.3.节(参照标准)。Structures of known impurities, and validation of the analytical methods, should be provided (following the Specifications and Tests) and be referenced in section II.F.3. (Reference Standard). 所有主要的杂质应分别限定。应该提供每一种杂质的单位的最大量。如果有杂质的毒性信息或已设立了毒性限度,应当提供这些信息。All major impurities should be individually limited. The maximum amount per unit does of every individual impurity should be provided. If there is information on toxicity or information on toxic limits that have been set for these impurities, this information should be provided. 在动物和临床实验中使用的每批原料药,应当提供杂质的分析结果列表,列出所有杂质(单个与总杂质,并包括那些未知的)。A summary tabulation of the results from the analytical examination of individual batches of the drug substance used in animal and clinical testing, listing all impurities (individually as well as total, and including those which are unidentified), should be provided. (5)含量测定Assay 如果可能,对原料药的含量测定应该有专属性,因为它也用于稳定性研究。可以用同样的方法测量原料药和杂质(如:HPLC法)。由于需要一个专属的鉴别检验,所以用合适的方法(如:色谱法)能控制杂质的可能干扰时,化验的专属性不是最重要的;在这种情况下,可以采用非专属性的化验方法,如:电位滴定。The assay for the drug substance should be specific if possible, since it can then be used for stability-indicating purposes. It may be practical to measure the drug substance and impurities by the same procedure (e.g., high pressure liquid chromatography (HPLC)). Since a specific identity test is required, assay specificity is not essential when impurities which might interfere are controlled (and limited) by suitable (e.g., chromatographic) methods; in these circumstances non-specific assay methods, such as a potentiometric titration, may be employed. 新原料药DNA的制定一个含量的范围和杂质的限度,应该基于实际的生产结果(如:通过对单批产品的分析)。最好是按照实际储存条件下的化合物的稳定性,制定再检测日期。The assay limits established in the NDA for the new drug substance, as well as the limits for impurities, should be based on actual manufacturing results (i.e., from analyses of individual batches). A retest date, based on the stability of the compound under actual storage conditions, is desirable. 微粉化的原料应该检测粒度与粒度分布,这些通常在日常化验中不包括在内。通常化验项目如下: Microencapsulated compounds should also be tested for particle size and dissolution rate. Not included in this listing, but generally provided as part of the specifications and tests, are (1) 水份含量或干燥失重moisture content or loss on drying; (2) 炽残残渣residue on ignition; (3) 残留溶媒residual solvents; (4) 重金属heavy metals. 应该提供一个合理的物料平衡控制标准The specifications should provide a reasonable material balance. 七、固态原料药的控制 1、固态原料药与生物利用度的关系Solid-State Drug Substance Forms: Relationship to Bioavailability 有关法律要求,如果适用,应当用适当的控制参数来描述原料药的特征,以确保原料药的生物利用度(参见:21 CFR 314.50(3) (ii), 和 320.52(e)[4-1-85 版])。一些原料药的固态特性(如:多晶型或无定型,溶剂化作用或水合作用,各种包涵性复合物,粒度或比表面积),可能极大地影响着固态和悬浮态形式的制剂药品的溶出度与生物利用度。这些性质对溶液制剂和水溶性高的原料药不是很重要。The regulations require, where appropriate, specifications characterizing the drug substance so as to assure the bioavailability of the drug product (see 21 CFR 314.50(3) (ii), and 320.52(e)[4-1-85 edition]). Certain solid-state properties of the drug substance (e.g., polymorphic form or amorphism, solvation or hydration, various types of inclusion complexes, and particle size or surface area) may profoundly affect dissolution and bioavailability from solid dosage forms or suspension drug products. These properties are less important for solution dosage forms and for drug substances which are highly water soluble. 对难溶性原料药(如:灰黄霉素、呋喃妥因),粒度的大小对药物的作用影响很大,粒度的大小不同也可能会影响原料药的毒性。For drug substances with limited aqueous solubility (e.g., griseofulvin, nitrofurantoin), particle size can have a large effect on the behavior of the drug product, and significant differences in particle size may also affect toxicity. 当存在生物利用度的问题或原料药是从多个来源获得时,鉴别、检验、控制固体形态的差异显得尤其重要。Identifying, characterizing, and controlling the differences in solid-state forms is especially important when a bioavailability problem exists and/or the drug substance is obtained from multiple sources. 提交新药申请(NDA)数据时,申请者应该已确定药品是否存在于多种固体形态以及其是否影响药品的溶出度与生物利用度,粒度的大小对药品的溶出度与生物利用度是很重要。没有必要用与合成工艺无关的技术去“制造”另外的固体形态。By the time of an NDA submission, the applicant should have established whether (or not) the drug substance exists in multiple solid-state forms, whether these affect the dissolution and bioavailability of the drug product, and whether particle size is important for dissolution and bioavailability of the drug product. It is not necessary to `create' additional solid-state forms by techniques or conditions irrelevant to the synthetic process. 申请者应该提供信息说明为何和怎样得出以下结论The applicant should provide information describing how and why it has been concluded that (a) 当药品按照新药申请(NDA)中的方法进行生产和储存时,没有发生固体形态 改变;a change in solid-state form does not occur when the drug substance is manufactured and stored according to the NDA directions; or (b) 产生了不同的形态但没有导致生物利用度的问题different forms occur but do not result in a bioavailability problem; or (c) 多态现象、溶剂化作用或粒度大小对生物利用度有重要影响polymorphism, solvation, or particle size has an important effect on bioavailability. 应该简要描述化验方法并证明其是合适的。对于(a) 和 (b)两种情况,适用性是指有关程序能够检测和区分多晶型物(或溶媒化物)。对于情况(c),适用性是指该程序可以检测和估计混合物中的多晶型物和溶剂化物,或者它可以测量颗粒尺寸。The test methods used should be briefly described and be shown to be suitable. In cases (a) and (b), suitability means that the procedure(s) can, with reasonable certainty, detect and distinguish between polymorphs (or solvates) should they occur. For case (c), suitability means that the procedure(s) can detect and quantitate polymorphs and/or solvates in admixtures of such forms, or measure particle size. 为了生产所需要的固体形态的原料药,应该建立适度的生产和控制程序(如果需要,包括在线的中控)。应该强调的是,生产工艺(或储存条件)对生产特定的同质多形异构体或溶剂化物是直接相关的。控制方法只是决定结果。Appropriate manufacturing and control procedures (including in-process testing when needed) should be established for the production of the desired solid-state form(s). It should be emphasized that the manufacturing process (or storage condition) is responsible for producing particular polymorphs or solvates; the control methods merely determine the outcome. 当考虑具体的固体形态的差异时,就会发现其中有互相依赖的关系,因此,如有可能,应该对相同颗粒大小的样品进行比较。While specific kinds of differences in solid-state forms are considered separately below, there is some interdependence; thus comparisons should, if possible, be performed on samples of similar particle size. 2、多态现象Polymorphism 由于晶体点阵的分子排列不同,一些原料药以几种不同的晶型存在(多晶型物),这样他们显示了不同的物理性质。同样的原料药也存在于非晶形态中。这些不同的形态在熵能含量上不同,但在构成上相同。影响多态现象(或溶剂化物)的关键因素是最终溶媒和分离条件的选择。参见之前的注释(II.D.2.d.)。Some drug substances exist in several different crystalline forms ("polymorphs"), due to a different arrangement of molecules in the crystal lattice, which thus show distinct differences in their physical properties. The same drug substance may also exist in a noncrystalline (amorphous) form. These various forms differ in their thermodynamic energy content, but not in composition. One of the critical factors affecting polymorphism (or solvation) is the choice of final solvent and isolation conditions in the synthesis. As noted previously (II.D.2.d.), 当最终结晶溶媒发生改变时,必须有证据证明没有发生固体形态的转型改变。常规的储存条件以及一些产品的制造条件(如:药片压制或在颗粒化过程中使用一种有机溶媒)也会导致转型。问题是:晶型是否稳定,或它是否是依赖于时间和工艺? when a change is made in the final crystallization solvent, evidence must be provided that no transformation in solid-state form has occurred. Routine storage conditions, as well as some conditions of product manufacture (e.g., tablet compression, or use of an organic solvent during granulation) may also cause transformations. The question is: Is the crystalline (or amorphous) form stable, or is it time and/or process dependent? 应该用合适的分析程序来判断是否有多晶型态现象发生。以下是一些物理化学测量的例子和技术:Appropriate analytical procedures should be used to determine whether (or not) polymorphism occurs. Some examples of physico-chemical measurements and techniques are (1) 熔点 (包括:热态镜检法) melting point (including hot-stage microscopy); (2) 红外线光谱(不在溶媒中)infrared spectra (not in solution); (3) X光颗粒衍射;X-ray powder diffraction; (4) 热分析方法(如:差示扫描量热法(DSC)),示差热分析(DTA), 热解重量分析TGA));t hermal analysis methods (e.g., differential scanning calorimetry (DSC), differential thermal analysis (DTA), thermogravimetric analysis (TGA)); (5) 拉曼光谱学Raman spectroscopy; (6) 比较的内在溶出速率 C omparative intrinsic dissolution rate; (7) 电子显微镜扫描 (SEM)scanning electron microscopy (SEM). 这些方法不是按其鉴别和测定能力排列的。申请者有责任选择方法用以提供有关多态现象的证据,如果生物利用度受到了影响,也应该提供和证明有关控制固体形态药品的规格和检验的适用性的内容。These methods are not ranked in order of their discriminating or quantitating ability. It is the applicant's responsibility to select the method(s) used to provide evidence concerning polymorphism, and if bioavailability is affected, to provide and demonstrate the suitability of the specifications and tests (including preparation and provision of reference standards) for the control of the solid-state form of the drug substance. 3、溶剂化物(包括水合作用)Solvation (including hydration) 制造和储存原料药的条件可能会导致离析或形成溶剂化物或水化的原料药。这通常可以通过干燥法检测,或者通过卡尔菲舍滴定法(对水合物)检测。其它方法(如:TGA)提供的信息可能也是必要的,因为有些溶剂化物通常在溶剂的沸点以上是稳定的。当溶剂化作用或水合作用影响到生物利用度时,应建立适当的制造和控制程序。Conditions used in manufacture and/or storage of the drug substance may result in the isolation or formation of a solvated or hydrated drug substance. This is most directly assessed by testing for loss on drying (LOD) or by Karl Fischer titration (for hydrates). Information from other methods (e.g., TGA) may be necessary, because some solvates are known to be stable at temperatures above the boiling point of the solvent. When solvation or hydration affects bioavailability, appropriate manufacturing and control procedures should be established. 4、粒度大小(和表面面积)Particle Size (and surface area) 原料药的粒度分布和表面面积可能会影响药品的溶出度与生物利用度。所以,申请者要改变粒度分布和表面积以使药物具有更多的有利特性。对于难溶性的原料药(如:低于每毫升5毫克的)在标明检测限度的情况下,应当说明具有代表性粒度分布和任何改变程序后的粒度分布。也应该提供原料药粒度分布对溶出度(制剂产品)影响的情况。当原料药的粒度分布/表面积与制剂产品的生物利用度有关的时候,应该提供有关改变粒度分布/表面积的程序描述和用于检测的方法。同时应该提供用于生产的控制规格和控制方法。Particle size distribution and surface area of the drug substance may affect the dissolution and bioavailability of the drug product. Therefore, an applicant may conduct operations to alter particle size/surface area in order to achieve more favorable properties for the drug substance. For drug substances with low aqueous solubility (e.g., less than 5 milligrams per milliliter) both the typical original particle size distribution and the particle size distribution after any alteration procedures should be presented (preferably graphically), with detection limits indicated. The effect of drug substance particle size on dissolution (of the drug product) should also be provided. When particle size/surface area of the drug substance is relevant to the bioavailability of the drug product, the description of the procedure(s) used to alter particle size/surface area and the methods used for examination should be provided, and appropriate specifications and tests established for control. a. Pivotal intermediate - means an intermediate which may be prepared by more than one manufacturing process to provide material of suitable quality for use in the production of a drug substance. b. Key intermediate - means an intermediate in which an essential molecular characteristic(s) is first introduced into the structure and for which significant in-process controls are needed to ensure the purity of the drug substance. c. Final intermediate - means the last intermediate isolated and controlled during the manufacturing process; prior to the final step which provides the crude drug substance.